Lung cancer (Amsterdam, Netherlands) · 2026
MORPHEUS-Lung: biomarkers and clinical response to atezolizumab + bevacizumab + stereotactic body radiotherapy in patients with metastatic non-small cell lung cancer.
Клиническое исследование I фазыКлиническое исследование II фазыСтатьяМногоцентровое исследованиеРандомизированное исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Cho Byoung Chul, Lim Sun Min, Lee Sang Hoon, Kim Dong Kwon, Pardo Nuria, Prizant Hen, Lawrence Yaacov R, Al-Sakaff Nedal, Helms Hans-Joachim, Gayevskiy Velimir, Nabet Barzin Y, Pintoffl Jan, Ghiringhelli Francois
Аннотация
INTRODUCTION: Results from the MORPHEUS-Lung (NCT03337698) study suggest that atezolizumab + bevacizumab + stereotactic body radiotherapy (SBRT) was associated with numerically improved efficacy outcomes vs docetaxel (control) in immune checkpoint inhibitor-exposed patients with metastatic non-small cell lung cancer. We report exploratory analyses to identify potential biomarkers associated with this clinical response.
METHODS: Tumor samples were analyzed for differential gene expression and pathway/immune subset gene signatures by single cell RNA-sequencing and further validated with bulk RNA-sequencing.
RESULTS: The biomarker-evaluable population included 58 patients from two cohorts (atezolizumab + bevacizumab + SBRT, n = 26; docetaxel [control], n = 32). In a discovery study, analyses of clinical benefit (CB) vs non-CB groups at baseline showed that resident-memory CD8 T cells (TRM) were significantly enriched (P = 0.027; Gini index: P = 0.018), and expression of CXCL10+ and FOLR2+ macrophages was increased in the CB group. Pre- and post-treatment analysis showed that expression of effector-memory CD45RA+ CD8 T cells(TEMRA), CD8 TRM, and FOLR2+ and FABP4+ macrophages were numerically increased post-treatment. Together these results led to the identification of curated T-cell- and macrophage-associated gene response signatures. Using a confirmatory cohort, gene signature expression aligned with survival outcomes for patients receiving atezolizumab + bevacizumab + SBRT.
CONCLUSIONS: These results suggest that activation of T cells and macrophages are associated with a favorable clinical response to atezolizumab + bevacizumab + SBRT. Moreover, CD8 TRM, CD8 exhausted T cells, and CXCL10+ macrophages may serve as potential biomarkers of response to atezolizumab + bevacizumab + SBRT treatment and potentially aid in tailored, precision medicine for individual patients.
METHODS: Tumor samples were analyzed for differential gene expression and pathway/immune subset gene signatures by single cell RNA-sequencing and further validated with bulk RNA-sequencing.
RESULTS: The biomarker-evaluable population included 58 patients from two cohorts (atezolizumab + bevacizumab + SBRT, n = 26; docetaxel [control], n = 32). In a discovery study, analyses of clinical benefit (CB) vs non-CB groups at baseline showed that resident-memory CD8 T cells (TRM) were significantly enriched (P = 0.027; Gini index: P = 0.018), and expression of CXCL10+ and FOLR2+ macrophages was increased in the CB group. Pre- and post-treatment analysis showed that expression of effector-memory CD45RA+ CD8 T cells(TEMRA), CD8 TRM, and FOLR2+ and FABP4+ macrophages were numerically increased post-treatment. Together these results led to the identification of curated T-cell- and macrophage-associated gene response signatures. Using a confirmatory cohort, gene signature expression aligned with survival outcomes for patients receiving atezolizumab + bevacizumab + SBRT.
CONCLUSIONS: These results suggest that activation of T cells and macrophages are associated with a favorable clinical response to atezolizumab + bevacizumab + SBRT. Moreover, CD8 TRM, CD8 exhausted T cells, and CXCL10+ macrophages may serve as potential biomarkers of response to atezolizumab + bevacizumab + SBRT treatment and potentially aid in tailored, precision medicine for individual patients.